Sections

Osteoporosis

Workup

Approach Considerations

The workup consists of appropriate laboratory studies to look for potential secondary causes of osteoporosis and to determine, if needed, what pharmacologic therapies for osteoporosis might be safe to utilize. Measurements of bone mineral density (BMD) to estimate the risk of fracture are indicated.

Conventional radiography is used for the qualitative and semiquantitative evaluation of osteoporosis; morphometry assesses the presence of fractures.^[113]Quantitative imaging methods commonly used are dual-energy x-ray absorptiometry (DXA) and quantitative computed tomography (QCT) scanning.^[113]In the United States, current diagnostic and treatment criteria for osteoporosis are based solely on QCT hip and DXA spine or hip T-score measurements.^{[114, 115]}

BMD should be measured at both the posteroanterior (PA) spine and hip in all patients undergoing DXA.^[5]Forearm BMD should be measured under the following circumstances:

Hip and/or spine cannot be measured or interpreted
Hyperparathyroidism
Very obese patients (over the weight limit for DXA table)

For information on American College of Radiology (ACR) recommendations for evaluating the appropriateness of BMD measurement tests for osteoporosis in patients at risk of developing this condition, see ACR Appropriateness Criteria for osteoporosis and bone mineral density. For assessment of fracture risk, numerous risk calculators are available for fracture prediction. The Fracture Risk Assessment Tool (FRAX) with BMD and the Garvan Frature Risk Calculator with BMD have the best performance according to areas under the receiver operating characteristic (ROC) curve (AUC).^[116]

Children and adolescents

The official position of the International Society for Clinical Densitometry (ISCD) is that “fracture prediction should primarily identify children at risk of clinically significant fractures” (eg, fracture of lower-extremity long bones, vertebral compression fractures, or two or more upper-extremity long-bone fractures).^[5]However, densitometric criteria alone should not be used to diagnose osteoporosis in children and adolescents. Rather, such a diagnosis in this population must be based on a low bone mineral content (BMC) or BMD in conjunction with a clinically significant fracture history. Fractures are considered clinically significant^[5]if one or more of the following are present:

Lower-extremity long-bone fracture
Vertebral compression fracture
Two or more upper-extremity long-bone fractures
Low BMC or BMD, defined as a BMC or areal BMD Z-score that is –2.0 or less, adjusted for age, sex, and body size, as appropriate

Laboratory Studies

Laboratory studies are used to exclude secondary causes of osteoporosis and to ensure that the selection of pharmacologic therapy for osteoporosis is appropriate, based on kidney function and serum calcium levels. Baseline studies are summarized in Tables 5 and 6, below.

Table 5. Baseline Laboratory Studies for Underlying Disorders in Osteoporosis (Open Table in a new window)

Baseline test	Disorder
Complete blood count (CBC)	CBC results may reveal anemia, as in sickle cell disease (patients with anemia, particularly those older than 60 years, should also be evaluated for multiple myeloma), and may raise the suspicion for alcohol abuse (in conjunction with results from serum chemistry tests and liver function tests)
Serum chemistry levels	Calcium levels can reflect underlying disease states (eg, severe hypercalcemia may reflect underlying malignancy or hyperparathyroidism; hypocalcemia can contribute to osteoporosis) Levels of serum calcium, phosphate, and alkaline phosphatase are usually normal in persons with primary osteoporosis, although alkaline phosphatase levels may be elevated for several months after a fracture Levels of serum calcium, phosphate, and alkaline phosphatase may be obtained to assess osteomalacia Creatinine levels may decrease with increasing parathyroid hormone (PTH) levels or may be elevated in patients with multiple myeloma Creatinine levels are also used to estimate creatinine clearance, which may indicate reduced renal function in elderly patients Magnesium is very important in calcium homeostasis^[117]; decreased levels of magnesium may affect calcium absorption and metabolism
Liver function tests	Increased levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), bilirubin, and alkaline phosphatase may indicate alcohol abuse An elevated level of alkaline phosphatase in combination with normal calcium, phosphate, and aminotransferase should prompt consideration of Paget disease
Thyroid-stimulating hormone (TSH) level	Thyroid dysfunction has been associated with osteoporosis and should therefore be ruled out^[118]
25-Hydroxyvitamin D level	This test assesses for vitamin D insufficiency; inadequate vitamin D levels can predispose persons to osteoporosis through a mechanism of secondary hyperparathyroidism If vitamin D insufficiency and bone pain are present, consider the alternative diagnosis of osteomalacia

An important study by Tannenbaum evaluated 173 healthy women (ages 46-87 years) for secondary causes of osteoporosis and found that 55 (32%) had a previously undiagnosed disorder of bone or mineral metabolism.^[119]Given that occult disorders are so common in patients with osteoporosis, minimal laboratory screening is indicated in all patients who present with decreased bone mass.

Table 6. Tests for Secondary Causes of Osteoporosis (Open Table in a new window)

Tests for Secondary Causes of Osteoporosis	Disorder
24-Hour urine calcium level	This study assesses for hypercalciuria and hypocalciuria
Parathyroid hormone (PTH) level	An intact PTH result is essential in ruling out hyperparathyroidism; an elevated PTH level may be present in benign familial hypocalciuric hypercalcemia
Thyrotropin level (if on thyroid replacement)	Experts are divided on whether to include thyrotropin testing, regardless of a history of thyroid disease or replacement; however, one study showed reduced femoral neck bone mineral density (BMD) in women with subclinical hypothyroidism and hyperthyroidism^[118]
Testosterone and gonadotropin levels in younger men with low bone densities	These tests may help evaluate a sex hormone deficiency as a secondary cause of osteoporosis
Urinary free cortisol level and tests for adrenal hypersecretion	These tests are used to exclude Cushing syndrome, which, although uncommon, can lead to rapidly progressive osteoporosis when the condition is present; a urine free cortisol value or overnight dexamethasone suppression test should be ordered in suspected cases
Serum protein electrophoresis (SPEP) and urine protein electrophoresis (UPEP)	These are used to identify multiple myeloma
Antigliadin, antiendomysial, and anti-tissue transglutaminase (TTG) IgA antibodies	These tests can help identify celiac disease. A concomitant total IgA level is needed for interpretation, in case of IgA deficiency.
Serum tryptase and urine N-methylhistamine	These tests help identify mastocytosis
Bone marrow biopsy	This study is obtained when a hematologic disorder is suspected

Biochemical Markers of Bone Turnover

Biochemical markers of bone turnover reflect bone formation or bone resorption. These markers (both formation and resorption) may be elevated in high-bone-turnover states (eg, early postmenopausal osteoporosis) and may be useful in some patients for monitoring early response to therapy.

Currently available serum markers of bone formation (osteoblast products) include the following:

Bone-specific alkaline phosphatase (BSAP)
Osteocalcin (OC)
Carboxyterminal propeptide of type 1 collagen (P1CP)
Aminoterminal propeptide of type 1 collagen (P1NP)

Currently available urinary markers of bone resorption (osteoclast products) include the following:

Hydroxyproline
Free and total pyridinolines (Pyd)
Free and total deoxypyridinolines (Dpd)
N-telopeptide of type 1 collagen cross-links (NTX-1) (also available as a serum marker)
C-telopeptide of type 1 collagen cross-links (CTX-1) (also available as a serum marker)

Currently available serum markers of bone resorption include the following:

Cross-linked C-telopeptide of type 1 collagen (ICTP)
Tartrate-resistant acid phosphatase 5b (TRAP-5b)
N-telopeptide of type 1 collagen cross-links (NTX-1) (also available as a urinary marker)
C-telopeptide of type 1 collagen cross-links (CTX-1) (also available as a urinary marker)

BSAP is nonspecific and can be mildly elevated in patients with fractures. In addition, patients with hyperparathyroidism, Paget disease, or osteomalacia can have elevations of BSAP. Serum OC levels, if high, indicate a high-turnover type of osteoporosis.^[120]Elevation of urinary NTX-1 (> 40 nmol bone collagen equivalent per mmol urinary creatine) indicates a high-turnover state.

The International Osteoporosis Foundation (IOF) and the International Federation of Clinical Chemistry (IFCC) Bone Marker Standards Working Group have identified P1NP and CTX-1 in serum to be the reference markers of bone turnover for bone formation and bone resorption, respectively, for the fracture risk prediction and monitoring of osteoporosis treatment.^[121] However, significant controversy still exists regarding the use of these biochemical markers, and concerns have been raised about intra-assay and interassay variability. Further study is needed to determine the clinical utility of these markers in osteoporosis management.

For more information, see Bone Markers in Osteoporosis.

Plain Radiography

Plain radiography is recommended to assess overall skeletal integrity. In particular, in the workup for osteoporosis, plain radiography may be indicated if a fracture is already suspected or if patients have lost more than 1.5 inches of height (see the following image).

Asymmetric loss in vertebral body height, without evidence of an acute fracture, can develop in patients with osteoporosis. These patients become progressively kyphotic (as shown) over time, and the characteristic hunched-over posture of severe osteoporosis develops eventually.

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Obtain radiographs of the affected area in symptomatic patients. Lateral spine radiography can be performed in asymptomatic patients in whom a vertebral fracture is suspected, in those with height loss in the absence of other symptoms, or in those with pain in the thoracic or upper lumbar spine (see the following image). A scoliosis series is useful for detecting occult vertebral fractures.

Severe osteoporosis. This radiograph shows multiple vertebral crush fractures. Source: Government of Western Australia Department of Health.

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Radiographic findings can suggest the presence of osteopenia, or bone loss, but cannot be used to diagnose osteoporosis. Osteopenia is suggested by a cortical width that is less than the medullary width. Radiographs may also show fractures or other conditions, such as osteoarthritis, disk disease, or spondylolisthesis.

Plain radiography is not as accurate as BMD testing. Because osteoporosis predominantly affects trabecular bone rather than cortical bone, radiography does not reveal osteoporotic changes until they affect the cortical bone. Cortical bone is not affected by osteoporosis until more than 30% of bone loss has occurred. Approximately 30-80% of bone mineral must be lost before radiographic lucency becomes apparent on radiographs.^[122]Thus, plain radiography is an insensitive tool for diagnosing osteoporosis.

Dual-Energy X-Ray Absorptiometry (DXA)

Several large prospective studies have shown that BMD measurements of the distal and proximal femur and the vertebral bodies can predict the development of the major types of osteoporotic fractures. BMD has been shown to be the best indicator of fracture risk. According to the National Osteoporosis Foundation (NOF), evaluating BMD on a periodic basis is the best way to monitor bone mass and future fracture risk,^{[4, 6]}although there is controversy about how frequently to measure this.^[123]

DXA is currently the criterion standard for the evaluation of BMD.^{[5, 6]}Compared with other screening tools (eg, calcaneal quantitative ultrasonography, the Simple Calculated Osteoporosis Risk Estimation [SCORE]), DXA has been found to be efficacious and cost-effective.^[124]DXA is not as sensitive as quantitative computed tomography (QCT) scanning for detecting early trabecular bone loss, but it has comparable costs,^[124]it is done on an outpatient basis,^[4]and there are no special requirements for performing it. Also, radiation exposure is kept to a minimum.

DXA is used to calculate BMD at the lumbar spine, hip, and proximal femur (see the images below). Densitometric spine imaging can be performed at the time of DXA scanning to detect vertebral fractures. Not all DXA machines are capable of performing vertebral fracture assessment (VFA), but when available, VFA should be considered if the results may influence clinical management of the patient.^[125]

Example of a dual energy x-ray absorption (DXA) scan. This image is of the left hip bone. Source: Government of Western Australia Department of Health.

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Example of a dual energy x-ray absorption (DXA) scan. This image is of the lumbar spine. Source: Government of Western Australia Department of Health.

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Although measurement of BMD at any site can be used to assess overall fracture risk, measurement at a particular site is the best predictor of fracture risk at that site. Whenever possible, the same technologist should perform subsequent measurements on the same patient using the same machine. This method can be used in both adults and children. Factors that may result in a falsely high BMD determination include spinal fractures, osteophytosis, scoliosis, and extraspinal (eg, aortic) calcification.

Bone density data from a DXA are reported as T-scores and Z-scores. The T-score is the value compared to that of control subjects who are at their peak BMD, whereas the Z-score reflects a value compared to that of patients matched for age and sex.^{[7, 8, 9, 10]}

WHO T-score and Z-score criteria

World Health Organization (WHO) criteria define a normal T-score value as within 1 standard deviation (SD) of the mean BMD value in a healthy young adult. Values lying farther from the mean are stratified as follows^[9]:

T-score of –1 to –2.5 SD indicates osteopenia (low bone mass)
T-score of less than –2.5 SD indicates osteoporosis
T-score of less than –2.5 SD with fragility fracture(s) indicates severe osteoporosis

For each SD reduction in BMD, the relative fracture risk is increased 1.5-3 times. Of note, about half of osteoporotic fractures occur in women with a T-score greater than –2.5, and the other half occur in those with a T-score lower than –2.5, the WHO’s cutoff for DXA-based diagnosis of osteoporosis.

This diagnostic classification should not be applied to premenopausal women, men younger than 50 years, or children. Instead, Z-scores adjusted for ethnicity or race should be used, with values of –2.0 SD or lower defined as "below the expected range for age" and those above –2.0 SD being "within the expected range for age." The diagnosis of osteoporosis in these groups should not be based on densitometric criteria alone.

International Society of Clinical Densitometry (ISCD) positions

The following are the official positions of the ISCD on peripheral DXA (pDXA)^[5]:

pDXA can be used in postmenopausal women for fracture risk assessment (vertebral and global fragility fracture risk), although its vertebral fracture predictive ability is weaker than central DXA and heel quantitative ultrasonography (QUS); evidence for use in men is insufficient
The WHO diagnostic classification can be applied only to DXA at the femoral neck, total femur, lumbar spine, and the 33% radius region of interest (located in the distal forearm) measured by DXA or pDXA devices utilizing a validated young-adult reference database
If central DXA cannot be done, radius pDXA measurements can be used to identify patients in whom pharmacologic treatment should be initiated; the fracture probability, based on both device-specific thresholds and clinical risk factors, should be high in those patients
pDXA cannot be used to monitor the effects of osteoporosis treatments

Measurements of bone strength

Measurements of bone strength that can be obtained by DXA, with appropriate software, include hip structural analysis (HSA) and trabecular bone scores (TBS). An additional technique for measurement of bone strength, finite element analysis (FEA), can be based on either computed tomography (CT) or DXA .

Hip structural analysis

HSA uses data obtained from DXA examinations to estimate structural properties of the femur. Specifically, estimated parameters such as femoral neck cross-sectional moment of inertia, hip axis length, and cross sectional area parameters can be combined with clinical characteristics (eg, age, weight, ethnicity) to calculate the femoral strength index, which is ultimately an estimate of how well the femur can withstand a direct impact to the greater trochanter.^[126]

HSA measurements have been found to correlate well with other measures of bone density such as DXA-derived BMD and quantitative CT^[127]but have not consistently demonstrated superiority.^[128]Furthermore, the ability of HSA to determine bending strength is limited to the specific plane of the image; comparisons require consistent and correct positioning, which has proven a hindrance to widespread clinical use.^{[129, 130]}

Trabecular bone scores

TBS are another DXA-derived measurement of bone strength. TBS uses “gray-level texture measurements” from two-dimensional DXA scans of the lumbar spine to derive bone strength parameters.^[131]TBS may complement standard measures of BMD.^[132]

Finite element analysis

Traditional methods of measuring bone density (eg, DXA), while inexpensive and easy to perform, do not account for all the material properties of bone. In fact, many females, and even more males, who sustain hip fractures have BMDs above the osteoporotic threshold.^[133]FEA is a relatively new technique for measuring fracture risk that is emerging as a highly accurate tool to evaluate bone strength.

With FEA, three-dimensional renderings of bone created using CT images^[134]or DXA^[135]are subjected to computer-simulated loads until fracture. This technique for measuring bone strength is mostly used in research settings, but has the potential for future clinical use.^[136]

Quantitative Computed Tomography

Quantitative computed tomography (QCT) is another method employed to measure BMD. At the spine, it measures BMD as a true volume density in g/cm³, which is not influenced by bone size. This technique can be used in both adults and children. QCT scanning of the spine is the most sensitive method for diagnosing osteoporosis, because it measures trabecular bone within the vertebral body.^[137]At the hip, QCT produces DXA-equivalent T-scores and BMD measures in g/cm².^{[114, 115]}

QCT scanning may be useful in identifying fractures. It can be used to identify not only the fracture line but also areas of callus formation and sclerosis, consistent with healing fracture. It may also be used for evaluation of metastatic bone disease.

Compared with DXA scanning, QCT has a comparable cost^[124]and precision.^{[114, 138, 139, 140]}In addition, as with DXA, no dye injection should be used.^[141]QCT is a very sensitive technique when repeated measurements are needed to detect small changes in BMD, and modern three-dimensional (3D) QCT acquisition has a scan time less than 10 seconds for the lumbar spine or proximal femur, and there is no interference by osteophytes.^{[142, 143]}However, QCT requires a higher radiation dose.^[143]

Nonetheless, QCT scanning is less commonly used than DXA; based on US Medicare data, about 5% of all BMD assessments are done with QCT scanning. Smaller, rural hospitals may favor QCT scanning, as they often already have a CT scanner for trauma cases and may not be able to afford a DXA machine as well.

International Society of Clinical Densitometry positions

The following are the official positions of the International Society of Clinical Densitometry (ISCD) on QCT of the lumbar spine^[5]

When using single-slice QCT, L1-L3 should be scanned; with 3D QCT, L1-L2 should be scanned
QCT of the spine can be used to predict vertebral fractures in postmenopausal women, but there is insufficient evidence to recommend spine QCT for spinal fracture prediction in men or hip fracture prediction in both women and men
Peripheral QCT (pQCT) of the forearm at the ultra-distal radius predicts hip, but not spine, fragility fractures in postmenopausal women; there is lack of sufficient evidence to support this position for men
Because T-scores by QCT are not equivalent to T-scores based on DXA, the World Health Organization (WHO) diagnostic classification of osteoporosis cannot be used
If central DXA measurements cannot be obtained, QCT of the spine or pQCT of the radius can be used to identify patients who are appropriate candidates for pharmacologic treatment; fracture probability based on both device-specific thresholds and clinical risk factors should be high in those patients
QCT of the spine can be used to monitor age-, disease- and treatment-related BMD changes via trabecular BMD of the lumbar spine

The following are the official positions of the ISCD on pQCT of the radius^[5]:

pQCT of the forearm at the ultra-distal radius cannot be used for fracture risk assessment of the spine, but does predict hip fragility fractures in postmenopausal women
There is insufficient evidence to recommend pQCT for fracture risk prediction in men
As with QCT of the spine, pQCT of the radius cannot be used to diagnose osteoporosis based on the WHO diagnostic classification
As with QCT of the spine, pQCT of the radius along with clinical risk factors can be used to initiate pharmacologic treatment if central DXA cannot be obtained
pQCT measurements of the trabecular and total BMD of the ultra-distal radius can be used to monitor age-related BMD changes

Single-Photon Emission CT

Single-photon emission computed tomography (SPECT) scanning represents a tomographic (CT-like) bone imaging technique that offers better image contrast and more accurate lesion localization than planar bone scanning. It increases the sensitivity and specificity of bone scanning for detection of lumbar spine lesions by 20-50% over planar techniques.

SPECT scanning is helpful when accurate localization of skeletal lesions within large and/or anatomically complex bony structures is required. This localization is possible because SPECT can visualize bony structures that would overlap on planar images (eg, separating vertebral body, facet and pars interarticularis lesions).

Quantitative Ultrasonography

Quantitative ultrasonography (QUS) of the calcaneus is a low-cost portable screening tool. It has the advantage of not involving radiation, but it is not as accurate as other imaging methods. Ultrasonography cannot be used for monitoring skeletal changes over time, nor can it be used to monitor the response to treatment, because of its lack of precision.

International Society of Clinical Densitometry positions

The following are the official positions of the ISCD on QUS^[5]:

Bone density measurements from QUS devices should be independently validated; measurements by different devices cannot be directly compared
The heel is the only validated skeletal site for the clinical use of QUS in osteoporosis management
Validated calcaneal QUS devices can be used in postmenopausal women to predict hip, vertebral, and global fracture risk, and in men older than 65 years to predict hip and all nonvertebral fractures
The WHO diagnostic classification cannot be applied to T-scores from QUS measurements
If central DXA cannot be obtained, calcaneal QUS in combination with clinical risk factors can be used to identify patients in whom pharmacologic treatment should be initiated
Calcaneal QUS plus clinical risk factors can also be used to identify patients at very low fracture probability in whom no further diagnostic testing is necessary
QUS cannot be used to monitor the skeletal effects of treatments for osteoporosis

Magnetic Resonance Imaging

Magnetic resonance imaging (MRI) may be useful in identifying fractures and in the assessment of metabolic bone disease. Using fat-suppression sequences, marrow edema consistent with fracture may be noted as areas of hypointensity on T1-weighted images in association with corresponding areas of hyperintensity on T2-weighted images. MRI is a very sensitive modality and is believed by some to be the diagnostic imaging method of choice in the detection of acute fractures, such as sacral fractures.

MRI can be used to discriminate between acute and chronic fractures of the vertebrae and occult stress fractures of the proximal femur. These osteoporotic fractures demonstrate characteristic changes in the bone marrow that distinguish them from other uninvolved parts of the skeleton and the adjacent vertebrae.

Bone Scanning

Bone scans assesses the function and tissue metabolism of organs by using a radionuclide (technetium-99m [^99m Tc]) that emits radiation in proportion to its attachment to a target structure. This technique detects an increase in osteoblastic activity (as seen in compression fractures).

Images may be obtained in three phases of the bone scanning process (immediate-flow study, immediate static blood pool study, and delayed static study). Acute fractures are visible in all phases of bone scanning and may remain beyond the reference range for up to 2 years.

Bone Biopsy and Histologic Features

Bone biopsy can help to exclude underlying pathologic conditions, such as mastocytosis, that may be responsible for presumed osteoporotic fracture. Typically, iliac crest biopsy is performed either in the minor procedure suite or in the operating room.

Tetracycline double labeling is a process used to calculate data on bone turnover. In this procedure, patients are given tetracycline, which binds to newly formed bone. This appears on biopsy samples as linear fluorescence. A second dose of tetracycline is given 11-14 days after the first dose; this appears on a biopsy sample as a second line of fluorescence. The distance between the two fluorescent labels can be measured to calculate the amount of bone formed during that interval, which may potentially indicate that too little bone formation or too much bone resorption is the cause of osteoporosis in a patient. Tetracycline labeling may also help clinicians to test potential therapy (ie, did the treatment slow bone resorption, increase bone formation, or both?) and study other metabolic bone responses.

Histologic examination of osteoporotic bone may reveal generalized thinning of trabeculae and irregular perforation of trabeculae, reflecting unbalanced osteoclast-mediated bone resorption.^[73]The following images are of histologic specimens from patients with osteoporosis.

Osteoporosis is defined as a loss of bone mass below the threshold of fracture. This slide (methylmethacrylate embedded and stained with Masson's trichrome) demonstrates the loss of connected trabecular bone.

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The bone loss of osteoporosis can be severe enough to create separate bone "buttons" with no connection to the surrounding bone. This easily leads to insufficiency fractures.

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Inactive osteoporosis is the most common form and manifests itself without active osteoid formation.

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Osteoporosis that is active contains osteoid seams (red here in the Masson's trichrome).

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Woven bone arising directly from surrounding mesenchymal tissue.

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This image depicts bone remodeling with osteoclasts resorbing one side of a bony trabecula and osteoblasts depositing new bone on the other side.

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Osteoclast, with bone below it. This image shows typical distinguishing characteristics of an osteoclast: a large cell with multiple nuclei and a "foamy" cytosol.

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In this image, several osteoblasts display a prominent Golgi apparatus and are actively synthesizing osteoid. Two osteocytes can also be seen.

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Treatment & Management

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Media Gallery

Osteoporosis. Lateral radiograph demonstrates multiple osteoporotic vertebral compression fractures. Kyphoplasty has been performed at one level.
Osteoporosis. Lateral radiograph of the patient seen in the previous image following kyphoplasty performed at 3 additional levels.
Osteoporosis of the spine. Observe the considerable reduction in overall vertebral bone density and note the lateral wedge fracture of L2.
Osteoporosis of the spine. Note the lateral wedge fracture in L3 and the central burst fracture in L5. The patient had suffered a recent fall.
Normal femoral anatomy.
Stable intertrochanteric fracture of the femur.
Percutaneous vertebroplasty, transpedicular approach.
Asymmetric loss in vertebral body height, without evidence of an acute fracture, can develop in patients with osteoporosis. These patients become progressively kyphotic (as shown) over time, and the characteristic hunched-over posture of severe osteoporosis develops eventually.
In kyphoplasty, a KyphX inflatable bone tamp is percutaneously advanced into the collapsed vertebral body (A). It is then inflated, (B) elevating the depressed endplate, creating a central cavity, and compacting the remaining trabeculae to the periphery. Once the balloon tamp is deflated and withdrawn, the cavity (C) is filled under low pressure with a viscous preparation of methylmethacrylate (D).
Osteoporosis is defined as a loss of bone mass below the threshold of fracture. This slide (methylmethacrylate embedded and stained with Masson's trichrome) demonstrates the loss of connected trabecular bone.
The bone loss of osteoporosis can be severe enough to create separate bone "buttons" with no connection to the surrounding bone. This easily leads to insufficiency fractures.
Inactive osteoporosis is the most common form and manifests itself without active osteoid formation.
Osteoporosis that is active contains osteoid seams (red here in the Masson's trichrome).
Woven bone arising directly from surrounding mesenchymal tissue.
This image depicts bone remodeling with osteoclasts resorbing one side of a bony trabecula and osteoblasts depositing new bone on the other side.
Osteoclast, with bone below it. This image shows typical distinguishing characteristics of an osteoclast: a large cell with multiple nuclei and a "foamy" cytosol.
In this image, several osteoblasts display a prominent Golgi apparatus and are actively synthesizing osteoid. Two osteocytes can also be seen.
Severe osteoporosis. This radiograph shows multiple vertebral crush fractures. Source: Government of Western Australia Department of Health.
Lateral spine radiograph depicting osteoporotic wedge fractures of L1-L2. Source: Wikimedia Commons.
Dual-energy computed tomography (CT) scan in a patient with involutional osteoporosis. Insufficiency fractures of the sacrum and the pubic rami are seen on an isotopic bone scan as a characteristic H, or Honda, sign (arrows), which appears as intense radiopharmaceutical uptake at the fracture sites.
Schematic example of an early bone densitometer: the QDR-1000 System (spine scan). (From: Third National Health and Nutrition Examination Survey Bone Densitometry Manual. Rockville, Md: Westat, Inc; 1989 [revised].)
Bone density scanner. This machine measures bone density to check for osteoporosis in the elderly and other vulnerable subjects. Source: Wikimedia Commons.
Example of a dual energy x-ray absorption (DXA) scan. This image is of the left hip bone. Source: Government of Western Australia Department of Health.
Example of a dual energy x-ray absorption (DXA) scan. This image is of the lumbar spine. Source: Government of Western Australia Department of Health.

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Table 1. WHO Definition of Osteoporosis Based on BMD Measurements by DXA

Definition	Bone Mineral Density Measurement	T-Score
Normal	BMD within 1 SD of the mean bone density for young adult women	T-score ≥ –1
Low bone mass (osteopenia)	BMD 1–2.5 SD below the mean for young adult women	T-score between –1 and –2.5
Osteoporosis	BMD ≥2.5 SD below the normal mean for young-adult women	T-score ≤ –2.5
Severe or “established” osteoporosis	BMD ≥2.5 SD below the normal mean for young-adult women in a patient who has already experienced ≥1 fracture	T-score ≤ –2.5 (with fragility fracture[s])
Sources: (1) World Health Organization (WHO). WHO scientific group on the assessment of osteoporosis at primary health care level: summary meeting report. Available at: https://www.who.int/chp/topics/Osteoporosis.pdf. Accessed August 21, 2020^[18] (2) Kanis JA. Assessment of fracture risk and its application to screening for postmenopausal osteoporosis: synopsis of a WHO report. WHO Study Group. Osteoporos Int. Nov 1994;4(6):368-81.^[10] (3) Czerwinski E, Badurski JE, Marcinowska-Suchowierska E, Osieleniec J. Current understanding of osteoporosis according to the position of the World Health Organization (WHO) and International Osteoporosis Foundation. Ortop Traumatol Rehabil. Jul-Aug 2007;9(4):337-56.^[9] BMD = bone mineral density; DXA = dual x-ray absorptiometry; SD = standard deviation; T-score = a measurement expressed in SD units from a given mean that is equal to a patient's BMD measured by DXA minus the value in a young healthy person, divided by the SD measurement in the population.

Table 2. Types of Primary Osteoporosis

Type of Primary Osteoporosis	Characteristics
Juvenile osteoporosis	Usually occurs in children or young adults of both sexes Normal gonadal function Age of onset: usually 8-14 years Hallmark characteristic: abrupt bone pain and/or a fracture following trauma
Idiopathic osteoporosis
Postmenopausal osteoporosis (type I osteoporosis)	Occurs in women with estrogen deficiency Characterized by a phase of accelerated bone loss, primarily from trabecular bone Fractures of the distal forearm and vertebral bodies common
Age-associated or senile osteoporosis (type II osteoporosis)	Occurs in women and men as BMD gradually declines with aging Represents bone loss associated with aging Fractures occur in cortical and trabecular bone Wrist, vertebral, and hip fractures often seen

Table 3. Causes of Secondary Osteoporosis in Adults

Cause	Examples
Genetic/congenital	Renal hypercalciuria – one of the most important secondary causes of osteoporosis; can be treated with thiazide diuretics Cystic fibrosis Ehlers-Danlos syndrome Glycogen storage disease Gaucher disease Marfan syndrome Menkes steely hair syndrome Riley-Day syndrome Osteogenesis imperfecta Hemochromatosis Homocystinuria Idiopathic hypercalciuria Hypogonadal states
Hypogonadal states	Androgen insensitivity Anorexia nervosa/bulimia nervosa Female athlete triad Hyperprolactinemia Panhypopituitarism Premature menopause Turner syndrome Klinefelter syndrome
Endocrine disorders^[56]	Cushing syndrome Diabetes mellitus Acromegaly Adrenal insufficiency Estrogen deficiency Growth hormone deficiency Hypercortisolism Hyperparathyroidism Hyperthyroidism Hypogonadism Hypophosphatasia Pregnancy Porphyria Prolactinoma
Deficiency states and malabsorption syndromes	Alcoholism Anorexia nervosa Calcium deficiency Magnesium deficiency Protein deficiency Vitamin D deficiency^{[56, 57]} Bariatric surgery Celiac disease Cystic fibrosis Gastrectomy Malnutrition Parenteral nutrition Chronic liver disease
Inflammatory diseases	Inflammatory bowel disease/Crohn disease Ankylosing spondylitis Rheumatoid arthritis Systemic lupus erythematosus
Hematologic and neoplastic disorders	Hemochromatosis Hemophilia Leukemia Lymphoma Multiple myeloma Sickle cell anemia Systemic mastocytosis Thalassemia Metastatic disease
Medications	Anticonvulsants Antipsychotic drugs Antiretroviral drugs Aromatase inhibitors Chemotherapeutic/transplant drugs: cyclosporine, tacrolimus, platinum compounds, cyclophosphamide, ifosfamide, high-dose methotrexate^[58] Furosemide Glucocorticoids and corticotropin^[59]: prednisone (≥5 mg/day for ≥3 mo)^[60] Heparin (long term) Hormonal/endocrine therapies: gonadotropin-releasing hormone (GnRH) agonists, luteinizing hormone-releasing hormone (LHRH) analogues, depomedroxyprogesterone, excessive thyroxine Lithium Proton pump inhibitors Selective serotonin reuptake inhibitors (SSRIs) SGLT2- inhibitors Thiazolidinediones
Miscellaneous	Amyloidosis Chronic metabolic acidosis Chronic heart failure Chronic obstructive pulmonary disease (COPD) Chronic or end-stage renal disease HIV/AIDS Idiopathic scoliosis Immobility Major Depression Multiple sclerosis Ochronosis Organ transplantation Renal insufficiency/ failure Renal tubular acidosis Sarcoidosis Weightlessness^[61]
Sources: (1) American Association of Clinical Endocrinologists medical guidelines for clinical practice for the prevention and treatment of postmenopausal osteoporosis: 2020 update. Endocr Pract. May2020; 26(Suppl 1):1-46.^[11] (2) Kelman A, Lane NE. The management of secondary osteoporosis. Best Pract Res Clin Rheumatol. Dec 2005;19(6):1021-37.^[54]

Table 4. Prevalence of Osteoporosis Among Racial and Ethnic Groups

Race/Ethnicity	Sex (age ≥50 y)	% Estimated to have osteoporosis	% Estimated to have low bone mass
Non-Hispanic white; Asian	Women	15.8	52.6
Non-Hispanic white; Asian	Men	3.9	36
Non-Hispanic black	Women	7.7	36.2
Non-Hispanic black	Men	1.3	21.3
Hispanic	Women	20.4	47.8
Hispanic	Men	5.9	38.3
Source: Wright NC, Looker AC, Saag KG, Curtis JR, Delzell ES, Randall S, et al. The recent prevalence of osteoporosis and low bone mass in the United States based on bone mineral density at the femoral neck or lumbar spine. J Bone Miner Res. Nov 2014;29(11):2520-6. [QxMD MEDLINE Link].

Table 5. Baseline Laboratory Studies for Underlying Disorders in Osteoporosis

Baseline test	Disorder
Complete blood count (CBC)	CBC results may reveal anemia, as in sickle cell disease (patients with anemia, particularly those older than 60 years, should also be evaluated for multiple myeloma), and may raise the suspicion for alcohol abuse (in conjunction with results from serum chemistry tests and liver function tests)
Serum chemistry levels	Calcium levels can reflect underlying disease states (eg, severe hypercalcemia may reflect underlying malignancy or hyperparathyroidism; hypocalcemia can contribute to osteoporosis) Levels of serum calcium, phosphate, and alkaline phosphatase are usually normal in persons with primary osteoporosis, although alkaline phosphatase levels may be elevated for several months after a fracture Levels of serum calcium, phosphate, and alkaline phosphatase may be obtained to assess osteomalacia Creatinine levels may decrease with increasing parathyroid hormone (PTH) levels or may be elevated in patients with multiple myeloma Creatinine levels are also used to estimate creatinine clearance, which may indicate reduced renal function in elderly patients Magnesium is very important in calcium homeostasis^[117]; decreased levels of magnesium may affect calcium absorption and metabolism
Liver function tests	Increased levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), bilirubin, and alkaline phosphatase may indicate alcohol abuse An elevated level of alkaline phosphatase in combination with normal calcium, phosphate, and aminotransferase should prompt consideration of Paget disease
Thyroid-stimulating hormone (TSH) level	Thyroid dysfunction has been associated with osteoporosis and should therefore be ruled out^[118]
25-Hydroxyvitamin D level	This test assesses for vitamin D insufficiency; inadequate vitamin D levels can predispose persons to osteoporosis through a mechanism of secondary hyperparathyroidism If vitamin D insufficiency and bone pain are present, consider the alternative diagnosis of osteomalacia

Table 6. Tests for Secondary Causes of Osteoporosis

Tests for Secondary Causes of Osteoporosis	Disorder
24-Hour urine calcium level	This study assesses for hypercalciuria and hypocalciuria
Parathyroid hormone (PTH) level	An intact PTH result is essential in ruling out hyperparathyroidism; an elevated PTH level may be present in benign familial hypocalciuric hypercalcemia
Thyrotropin level (if on thyroid replacement)	Experts are divided on whether to include thyrotropin testing, regardless of a history of thyroid disease or replacement; however, one study showed reduced femoral neck bone mineral density (BMD) in women with subclinical hypothyroidism and hyperthyroidism^[118]
Testosterone and gonadotropin levels in younger men with low bone densities	These tests may help evaluate a sex hormone deficiency as a secondary cause of osteoporosis
Urinary free cortisol level and tests for adrenal hypersecretion	These tests are used to exclude Cushing syndrome, which, although uncommon, can lead to rapidly progressive osteoporosis when the condition is present; a urine free cortisol value or overnight dexamethasone suppression test should be ordered in suspected cases
Serum protein electrophoresis (SPEP) and urine protein electrophoresis (UPEP)	These are used to identify multiple myeloma
Antigliadin, antiendomysial, and anti-tissue transglutaminase (TTG) IgA antibodies	These tests can help identify celiac disease. A concomitant total IgA level is needed for interpretation, in case of IgA deficiency.
Serum tryptase and urine N-methylhistamine	These tests help identify mastocytosis
Bone marrow biopsy	This study is obtained when a hematologic disorder is suspected

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Author

Rachel Elizabeth Whitaker Elam, MD, MSc Fellow, Department of Rheumatology, Medical College of Georgia at Augusta University

Rachel Elizabeth Whitaker Elam, MD, MSc is a member of the following medical societies: Alpha Omega Alpha, American College of Rheumatology, Georgia Society of Rheumatology

Disclosure: Nothing to disclose.

Coauthor(s)

Nicola Natasha Jackson, MBBS Resident Physician, Department of Internal Medicine, Piedmont Athens Regional Medical Center

Disclosure: Nothing to disclose.

Wambui Machua, MD Rheumatologist, Piedmont Hospital

Wambui Machua, MD is a member of the following medical societies: American College of Physicians, American College of Rheumatology, Atlanta Medical Association, Georgia Society of Rheumatology, International Society for Clinical Densitometry, Medical Association of Atlanta, Medical Association of Georgia

Disclosure: Nothing to disclose.

Laura D Carbone, MD, MS, FACP Professor, Department of Internal Medicine, Section Chief of Rheumatology, Medical College of Georgia at Augusta University and Charlie Norwood Veterans Affairs Medical Center

Laura D Carbone, MD, MS, FACP is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, American College of Rheumatology, American Medical Women's Association, American Society for Bone and Mineral Research, International Society for Clinical Densitometry, Society of General Internal Medicine

Disclosure: Nothing to disclose.

Chief Editor

Herbert S Diamond, MD Visiting Professor of Medicine, Division of Rheumatology, State University of New York Downstate Medical Center; Chairman Emeritus, Department of Internal Medicine, Western Pennsylvania Hospital

Herbert S Diamond, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, American College of Rheumatology, American Medical Association, Phi Beta Kappa

Disclosure: Nothing to disclose.

Additional Contributors

Kristine M Lohr, MD, MS Professor, Department of Internal Medicine, Interim Chief, Division of Rheumatology, Director, Rheumatology Training Program, University of Kentucky College of Medicine

Kristine M Lohr, MD, MS is a member of the following medical societies: American College of Physicians, American College of Rheumatology

Disclosure: Nothing to disclose.

Monique Bethel, MD Resident Physician, Department of Internal Medicine, Medical College of Georgia at Augusta University

Disclosure: Nothing to disclose.

Acknowledgements

Michael T Andary, MD, MS Professor, Residency Program Director, Department of Physical Medicine and Rehabilitation, Michigan State University College of Osteopathic Medicine

Michael T Andary, MD, MS is a member of the following medical societies: American Academy of Physical Medicine and Rehabilitation, American Association of Neuromuscular and Electrodiagnostic Medicine, American Medical Association, and Association of Academic Physiatrists

Disclosure: Allergan Honoraria Speaking and teaching; Pfizer Honoraria Speaking and teaching

Harris Gellman, MD Consulting Surgeon, Broward Hand Center; Voluntary Clinical Professor of Orthopedic Surgery and Plastic Surgery, Departments of Orthopedic Surgery and Surgery, University of Miami, Leonard M Miller School of Medicine

Harris Gellman, MD is a member of the following medical societies: American Academy of Medical Acupuncture, American Academy of Orthopaedic Surgeons, American Orthopaedic Association, American Society for Surgery of the Hand, and Arkansas Medical Society